Safety and pharmacokinetics of subcutaneous administration of broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs), given to HIV-1 exposed, uninfected neonates and infants: study protocol for a phase I trial.

Background: The ambitious goal to eliminate new pediatric HIV infections by 2030 requires accelerated prevention strategies in high-risk settings such as South Africa. One approach could be pre-exposure prophylaxis (PrEP) with broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs). The aim of our study is to define the optimal dose(s), the ideal combination(s) of bNAbs in terms of potency and breadth, and timing of subcutaneous (SC) administration(s) to prevent breast milk transmission of HIV.

Antioxidant Activity with Increased Endogenous Levels of Vitamin C, E and A Following Dietary Supplementation with a Combination of Glutathione and Resveratrol Precursors.

The effects of two different dietary supplements on the redox status of healthy human participants were evaluated. The first supplement (GluS, Glutathione Synthesis) contains the precursors for the endogenous synthesis of glutathione and the second (GluReS, Glutathione and Resveratrol Synthesis) contains in addition polydatin, a precursor of resveratrol. To assess the influence of GluS and GluReS on the redox status, ten thiol species and three vitamins were measured before (t0) and after 8 weeks (t1) of dietary supplementation.

A fast and reliable method for detecting SNP rs67384697 (Hsa-miR-148a binding site) by a single run of allele-specific real-time PCR.

Surface expression of human leukocyte antigen (HLA)-class I molecules is critical for modulating T/natural killer lymphocytes' effector functions. Among HLA molecules, HLA-C, the most recently evolved form of class I antigens, is subjected to both transcriptional and multiple post-transcriptional regulation mechanisms affecting its cell surface expression. Among the latter a region placed in the 3' untranslated region of HLA-C transcript contains the single nucleotide polymorphism (SNP) rs67384697 "G-ins/del" that has been found to be strictly associated with surface levels of HLA-C allomorphs because of the effect on the binding site of a microRNA (Hsa-miR-148a).

A Novel System to Discriminate HLA-C mir148a Binding Site by Allele-Specific Quantitative PC R.

The levels of expression of the HLA-class I molecules are critical for modulating T/NK lymphocytes effector functions. Among HLA molecules, HLA-C, the most recent developed form of class I antigens, is subjected to multiple post transcriptional level of regulation that affect its cell surface expression.We describe a new method of allele-specific real-time PCR that monitor the integrity/disruption of the binding site of the microRNA Hsa-miR-148a, a key factor associated to the levels of HLA-C expression in the Caucasian populations.

Corrigendum: HIV-1 Env associates with HLA-C free-chains at the cell membrane modulating viral infectivity.

This corrects the article DOI: 10.1038/srep40037.

Stability and Expression Levels of HLA-C on the Cell Membrane Modulate HIV-1 Infectivity.

HLA-C expression is associated with a differential ability to control HIV-1 infection. Higher HLA-C levels may lead to better control of HIV-1 infection through both a higher efficiency of antigen presentation to cytotoxic T lymphocytes and the triggering of activating killer immunoglobulin-like receptors on NK cells, whereas lower levels may provide poor HIV-1 control and rapid progression to AIDS. We characterized the relative amounts of HLA-C heterotrimers (heavy chain/β microglobulin [βm]/peptide) and HLA-C free heavy chains on peripheral blood mononuclear cells (PBMCs) from healthy blood donors harboring both alleles with stable or unstable binding to βm/peptide.

Activating Killer Immunoglobulin Receptors and HLA-C: a successful combination providing HIV-1 control.

Several studies demonstrated a relevant role of polymorphisms located within the HLA-B and -C loci and the Killer Immunoglobulin Receptors (KIRs) 3DL1 and 3DS1 in controlling HIV-1 replication. KIRs are regulatory receptors expressed at the surface of NK and CD8+ T-cells that specifically bind HLA-A and -B alleles belonging to the Bw4 supratype and all the -C alleles expressing the C1 or C2 supratype. We here disclose a novel signature associated with the Elite Controller but not with the long-term nonprogressor status concerning 2DS activating KIRs and HLA-C2 alleles insensitive to miRNA148a regulation.

HIV-1 Env associates with HLA-C free-chains at the cell membrane modulating viral infectivity.

HLA-C has been demonstrated to associate with HIV-1 envelope glycoprotein (Env). Virions lacking HLA-C have reduced infectivity and increased susceptibility to neutralizing antibodies. Like all others MHC-I molecules, HLA-C requires β-microglobulin (βm) for appropriate folding and expression on the cell membrane but this association is weaker, thus generating HLA-C free-chains on the cell surface.

Characterization of HIV-1 entry inhibitors with broad activity against R5 and X4 viral strains.

Background: Combined antiretroviral therapy has drastically reduced mortality and morbidity of HIV-infected individuals. Nevertheless long-term toxicity and appearance of viral resistance hampers the prolonged effectiveness of combination therapy, requiring a continuous input of drugs to replace those utilized in combination regimens. We here investigated the anti-HIV activity of novel derivatives of the suradista chemical class.

Comment on "Influence of HLA-C expression level on HIV control".

Apps et al. (Reports, 5 April 2013, p. 87) found that high human leukocyte antigen C (HLA-C) expression favors HIV-1 control.

Selected HIV-1 Env trimeric formulations act as potent immunogens in a rabbit vaccination model.

Background: Ten to 30% of HIV-1 infected subjects develop broadly neutralizing antibodies (bNAbs) during chronic infection. We hypothesized that immunizing rabbits with viral envelope glycoproteins (Envs) from these patients may induce bNAbs, when formulated as a trimeric protein and in the presence of an adjuvant.

Methods: Based on in vitro neutralizing activity in serum, patients with bNAbs were selected for cloning of their HIV-1 Env.

Characterization of humoral responses to soluble trimeric HIV gp140 from a clade A Ugandan field isolate.

Trimeric soluble forms of HIV gp140 envelope glycoproteins represent one of the closest molecular structures compared to native spikes present on intact virus particles. Trimeric soluble gp140 have been generated by several groups and such molecules have been shown to induce antibodies with neutralizing activity against homologous and heterologous viruses. In the present study, we generated a recombinant trimeric soluble gp140, derived from a previously identified Ugandan A-clade HIV field isolate (gp14094UG018).

Optimization of HIV-1 Envelope DNA Vaccine Candidates within Three Different Animal Models, Guinea Pigs, Rabbits and Cynomolgus Macaques.

HIV-1 DNA vaccines have many advantageous features. Evaluation of HIV-1 vaccine candidates often starts in small animal models before macaque and human trials. Here, we selected and optimized DNA vaccine candidates through systematic testing in rabbits for the induction of broadly neutralizing antibodies (bNAb).

Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor.

The natural history of HIV-1 infection is highly variable in different individuals, spanning from a rapidly progressive course to a long-term asymptomatic infection. A major determinant of the pace of disease progression is the in vivo level of HIV-1 replication, which is regulated by a complex network of cytokines and chemokines expressed by immune and inflammatory cells. The chemokine system is critically involved in the control of HIV-1 replication by virtue of the role played by specific chemokine receptors, most notably CCR5 and CXCR4, as cell-surface coreceptors for HIV-1 entry; hence, the chemokines that naturally bind such coreceptors act as endogenous inhibitors of HIV-1.

Rational design of HIV vaccine and microbicides: report of the EUROPRISE annual conference.

EUROPRISE is a Network of Excellence sponsored from 2007 to 2011 by the European Commission within the 6th Framework Program. The Network encompasses a wide portfolio of activities ranging from an integrated research program in the field of HIV vaccines and microbicides to training, dissemination and advocacy. The research program covers the whole pipeline of vaccine and microbicide development from discovery to early clinical trials.

Nef-specific CD45RA+ CD8+ T cells secreting MIP-1beta but not IFN-gamma are associated with nonprogressive HIV-1 infection.

Background: Long-term survival of HIV-1 infected individuals is usually achieved by continuous administration of combination antiretroviral therapy (ART). An exception to this scenario is represented by HIV-1 infected nonprogressors (NP) which maintain relatively high circulating CD4+ T cells without clinical symptoms for several years in the absence of ART. Several lines of evidence indicate an important role of the T-cell response in the modulation of HIV-1 infection during the acute and chronic phase of the disease.

Virological pattern of hepatitis B infection in an HIV-positive man with fatal fulminant hepatitis B: a case report.

Introduction: There seem to be no published data concerning the clinical impact of populations of hepatitis B virus (HBV) in the hepatic and extrahepatic compartments of HIV-infected people with severe acute hepatitis.

Case Presentation: A 26-year-old Caucasian man presenting to our hospital with clinical symptoms suggesting acute hepatitis was found to have an acute hepatitis B profile upon admission. He developed fatal fulminant hepatitis and was found to be heavily immunocompromised due to HIV-1 infection.

Improvement of CXCR3 ligand CXCL11/I-TAC measurement in human plasma and serum.

The chemokine receptor CXCR3 is involved in cell trafficking dysregulation associated with several inflammatory conditions, including autoimmune and viral diseases. Downregulation of CXCR3, through binding with its ligand CXCL11 (I-TAC), represents a key mechanism in lymphocyte recruitment. Determination of circulating I-TAC can provide useful information in the investigation of inflammatory/infectious conditions.

NF-kappa B modulates sensitivity to apoptosis, proinflammatory and migratory potential in short- versus long-term cultured human gamma delta lymphocytes.

Vgamma9 Vdelta2 T lymphocytes are involved in the immune response against hematological malignancies and certain pathogens through the recognition of nonpeptidic Ags expressed by tumors and infected cells. Being equipped with proinflammatory chemokine receptors, they participate to the early phases of inflammation acting as both effector and connector cells between innate and adaptive immunity. We show in this study that after initial TCR triggering short- and long-term cultured gammadelta lymphocytes differ in their susceptibility to activation-induced apoptosis and proinflammatory phenotype.

The intracellular detection of MIP-1beta enhances the capacity to detect IFN-gamma mediated HIV-1-specific CD8 T-cell responses in a flow cytometric setting providing a sensitive alternative to the ELISPOT.

Background: T-cell mediated immunity likely plays an important role in controlling HIV-1 infection and progression to AIDS. Several candidate vaccines against HIV-1 aim at stimulating cellular immune responses, either alone or together with the induction of neutralizing antibodies, and assays able to measure CD8 and CD4 T-cell responses need to be implemented. At present, the IFN-gamma-based ELISPOT assay is considered the gold standard and it is broadly preferred as primary assay for detection of antigen-specific T-cell responses in vaccine trials.

Immunomodulatory effects of bovine colostrum in human peripheral blood mononuclear cells.

Human and bovine colostrum (BC) contain a remarkable amount of bioactive substances, including antibodies towards many common pathogens of the intestinal and respiratory tract as well as growth factors, vitamins, cytokines and other proteic, lipidic and glucidic factors. In this study we investigated whether BC had any immunomodulatory effect on human peripheral blood mononuclear cells (PBMC) from healthy donors. To this aim we focused on the production of IL-12 and IFN-gamma, cytokines involved in the Th1 polarization required for a successful immune response towards intracellular pathogens, such as bacteria and viruses.

Favorable outcome of ex-vivo purging of monocytes after the reintroduction of treatment after interruption in patients infected with multidrug resistant HIV-1.

In multidrug resistant patients treatment interruptions allow the selection of archived wild-type drug-susceptible viruses that compete for the less fit drug-resistant strains. However, the selection of viruses with increased replicative capacity is often followed by a loss of CD4+ T cells. In addition, drug resistant variants later re-emerge limiting the overall clinical benefit of treatment interruption.

Virological responses in a patient with recent HIV-1 infection experiencing an EBV reactivation.

The dynamics of interactions between HIV and other viral agents and their reciprocal influence on the cellular immune response is not fully understood. A clinical report is here described regarding an EBV reactivation occurring during a recent HIV infection. The two viruses appear to act in a sequential manner, mutually influencing each other in their replication and leading to determine a clinical outcome in the patient under study.